RT has been shown to be an effective treatment for patients with cervical cancer who experience locoregional recurrence after surgery. In a study by Kim et al., the 5-year local failure-free survival and OS rates of patients with cervical cancer who underwent RT after experiencing post-surgical recurrence were 63.9% and 66%, respectively [18]. In another study, Kim et al. found that the 5-year PFS and OS rates after RT were 62.7% and 60.1%, respectively [13]. These studies showed far better survival rates than did those performed in the previous decade in which the 5-year OS rates were below 50% [16, 17]. Our study focused on RT-naïve patients with cervical SCC; these individuals achieved excellent estimated 5-year OS, PFS, and LC rates of 84%, 79%, and 91%, respectively. These superior clinical outcomes can be partially attributed to the pathological tumor type, higher RT dose, and lack of previous RT. The 5-year local failure-free survival and PFS rates for re-irradiated patients in Kim et al.’s study were only 47.1% and 33.2%, respectively, indicating that having previously received RT had a negative effect on treatment, likely owing to dose limitations and radiosensitivity [18].
Although surgeries such as pelvic exenteration are also treatment options for patients with cervical cancer who experience central pelvic relapse without pelvic wall involvement or extrapelvic spread, RT has its own advantages (most notably fewer complications). Pelvic exenteration is usually considered the only curative therapeutic approach, but it is associated with high surgery-related morbidity and mortality rates [19]; the survival rate is less than 50%, while mortality is nearly 5% [12, 20]. Other surgical methods such as laterally extended pelvic/endopelvic resection carry certain risks of injury to the nerve, bladder, or rectum, leading to impaired urination and defecation. Moreover, a shortened vaginal length after surgery greatly reduces the quality of life as well as the female sexual function index [21]. The curative effect of surgery is also limited in patients with human papillomavirus-associated cervical cancer, as only the upper segments of the vagina with visible tumor can be resected while the lower, virus-infected segments may continue to undergo oncogenic transformation, resulting in re-recurrence. As such, RT can address these limitations of surgery.
We found that the factors that significantly influenced the effectiveness of RT for patients with recurrence were tumor size and recurrence pattern. Previous studies have shown that an initial tumor diameter ≤4 cm was a predictor of favorable LC in patients with cervical cancer who experienced advanced vaginal recurrence [22]. In Zolciak-Siwinska et al.’s study, a recurrent tumor diameter >3 cm was a significant prognostic indicator as it negatively influenced OS, DFS, and LC in patients with recurrences in the cervix or vagina who underwent re-irradiation [23]. In our study, endovaginal recurrence was a significant predictor of more favorable OS, PFS, and LC. The treatment dose for tumors that recur extravaginally is dependent on the surrounding organs such as the bladder, rectum, and intestine; therefore, treatment is more difficult in such patients than it is in subjects who only require radical RT.
Since recurrent tumors that are paravaginal or invasive of surrounding organs are associated with a relatively poor prognosis, it was an important objective of our study to explore treatment that could improve survival in these patients. Through stratified analysis, we discovered that the RT dose significantly affected LC in patients with extravaginal recurrence; this was a most novel finding of this study. Few investigations have elucidated the relationship between RT dose and survival; hence, ours was the first to show that a higher EQD2 (≥70 Gy) was significantly associated with prolonged LC. Presently, EBRT and BT combined constitute the first radical concurrent chemoradiotherapy choice for patients with locally advanced cervical cancer; however, there is no consensus on the optimal mode of RT for central recurrent cervical cancer, or on whether EBRT and BT should be administered [11, 13, 15, 18, 24]. Compared to 3-dimensional conformal radiation therapy, intensity-modulated RT reduces the doses to (and irradiation volumes of) the small intestine, rectum, and bone marrow [25, 26], reducing the risk of acute and chronic gastrointestinal and urinary toxicity [27, 28]. However, intensity-modulated RT is not a substitute for BT [29]. The latter allows for a higher dose of radiation to the tumor while minimizing toxicity to adjacent tissues. Moreover, our study found that combination EBRT and BT was safer than administering EBRT while increasing the irradiation dose. Moreover, the development of computed tomography- or magnetic resonance imaging-guided 3D intracavitary/interstitial BT and the application of new techniques such as 3D printing are expected to further optimize the dose to the tumor region while reducing toxicities and complications [30–34].
Notably, higher irradiation doses have not been definitively shown to lead to improved OS or PFS, indicating that RT has limited systemic therapeutic benefits despite excellent LC. Chemotherapy is often recommended for patients with extrapelvic metastases or recurrent disease who are not candidates for RT or exenterative surgery. Another retrospective analysis performed at our institution found that the PFS of patients with intrapelvic cervical cancer recurrence who were treated with RT alone was superior to that of counterparts who underwent a combination of RT and chemotherapy (P = 0.005) [19]. Multivariate analysis of data from that study did not find that concurrent chemotherapy was superior to RT alone. However, it has been shown that the tumor volume before BT is an important prognostic factor in patients with advanced cervical cancer and that their prognosis is more favorable when the high-risk CTV is ≤30 cc [35, 36]. With the increase in volume, a higher RT dose is required to achieve an LC rate over 90% [35, 36]. Platinum-based concurrent chemotherapy could increase sensitivity and reduce distant metastasis [37] and might be able to shrink the tumor volume faster and achieve potential survival benefits, especially in patients with extravaginal recurrence.
The limitations of this study include its retrospective, non-randomized design and inconsistent management of treatment owing to the long duration of the study. Second, potential bias may have been introduced during patient selection for the initial surgery and treatment of recurrence. Third, there have been continuous advances in RT technology over the time span of the study, and the type of RT administered (i.e., EBRT with or without BT or 2D-BT versus 3D-BT) as well as the dose distribution and fractionation of EBRT and BT were designed according to both the tumor characteristics and RT instrumentation available at the time. Thus, it was difficult to analyze whether a specific type of RT technology or dose fractionation influenced survival; as such, additional, prospective multicenter studies are warranted.